2. Stereocontrol in Organic Reactions

21 Pages·2017·3.61 MB·English

by  桑野 良一

2. Stereocontrol in Organic Reactions 2) Highly endothermic reaction
• The energy diagram of a highly endothermic step (Fig b) indicates that the reactant reaches the
(1) Principles in selective organic reactions
transition state at late stage. Therefore, the transition state is similar in structure and energy to
(a) Curtin–Hammett principle
the product.
Selectivities are controlled by the relative energies of two transition states. The difference of
・ Selectivities, including stereoselectivity, would be affected by the relative energy of each
reactants or products does not affect the selectivity.
possible product.
• Curtin-Hammett principle is useful for considering selectivities of organic reactions, when the
reaction forms different products (C and D) from two substrates (or intermediates) (A and B) in
(a) highly exothermic reaction (b) highly endothermic reaction (c) other
rapid equilibrium with one another (eq. 1).
• The selectivity, [C]/[D], is equal to exp(–DDG‡/RT). Therefore, the selectivity depends on only TS‡ TS‡ TS‡
DDG‡, although DDG‡ = DG2‡ – (DG1‡ + DG). reactant product
• Even if the reactant (or intermediate) A is less stable than B, product C would be the major E E E
product when TS1 is more stable than TS2. similar similar
product reactant reactant product
• Avoid to discuss the selectivity with the structures of reactants (or intermediates).

k K k
C 1 A B 2 D (1) G. S. Hammond, J. Am. Chem. Soc., 1955, 77, 334.
See also, J. E. Leffler, Science, 1953, 117, 340.
TS2
TS1 ΔΔG‡
G ΔG1‡ ΔG2‡
A
ΔG B
C reactants
product D
product

J. I. Seeman, Chem. Rev., 1983, 83, 83.

(b) Hammond’s postulate
If two states, as for example, a transition state and an unstable intermediate, occur consecutively
during a reaction process and have nearly the same energy content, their interconversion will
involve only a small reorganization of the molecular structure.
The postulate is useful for predicting the property of the transition state in highly exothermic or
endothermic process (Figs a and b). Do not apply the postulate to the reactions, in which the
reactant is similar in potential energy to the product (Fig c).
1) Highly exothermic reaction
• The energy diagram of a highly exothermic step (Fig a) indicates that the reactant reaches the
transition state at early stage. Therefore, the transition state is similar in structure and energy
to the reactant.
・ Selectivities, including stereoselectivity, would be affected by the relative energy of each
reactant (or its conformer).

– 13 –
(2) Stereoselective reaction and prochirality Enantiotopic group (or atom) (pro-R/pro-S)
(a) Enantioselective reaction • When two equivalent groups (or atoms) are attached on a sp3-hybridized carbon, the reaction
1) Features occurring on one of the groups results in forming a new chiral center. Different enantiomers will
• Enantioselective reaction is the reaction that produces an optically active compound from an be obtained from the reactions on each group. The two equivalent groups are called
achiral or racemic starting material with an optically active reagent or catalyst. 'enantiotopic group'.
• It is ordinary that an achiral compound is converted into a 1:1 mixture of R- and S-products, if the • Prochirality of enantiotopic group can be indicated with descriptor pro-R or pro-S. The
reaction creates a new chiral center. Both pathways leading to R- and S-products proceed prochirality is assigned as follows:
through enantiomeric transition states, which have the same energy level each other. i) Determine the priority of the four substituents on the atom, which will become a chiral center
• The optically active reagent or catalyst can discriminate the prochirality of the substrate. after the enantioselective reaction. Here, one of the enantiotopic groups is tentatively assume
to be dominant over another.
ii) Determine the R/S configuration with the above tentative priority. When the configuration is
R, the prochirality of the substituent with higher priority is assigned to pro-R. Otherwise, the
O O OMgBr OMgBr
Ph 1H + MeM2gBr Me– a H Phb Me– Me PRhH or HPhS Me pMroecOh2irCality His pro-aS. c' If c > c', the tentative configuration is S. 3Me C1O2Me pro-R
Oδ– 3a Oδ– 3b HO H = b c TThhee pprroocchhiirraalliittyy ooff cc' iiss pprroo--SR.. 4H C1O2Me pro-S
TSa δ– TSb δ–
Me H H Me 3) Discrimination of enantiotopic faces
Ph Ph
• In most enantioselective reactions, a chiral reagent or catalyst discriminates two enantiotopic
E E
faces of the unsaturated bond in the substrate (or intermediate) to give the enantio-enriched
1 + 2 1 + 2 product (See the figure in the left column).
3a 3b
• After the stereoselective reaction, no unreacted unsaturated bond remains in the resulting

product. Therefore, the enantioselectivity of the reaction reflects the selection of the
• Commonly, the stereoselectivity in the enantioselective reaction, which is called enantioselectivity, enantiotopic faces.
is equivalent to the enantiomeric excess of the optically active product.
• There are two types of stereodiscrimination in enantioselective reaction. One involves the Examples
Me
discrimination of enantiotopic faces; another involves that of enantiotopic groups.
Me
BH
2) Prochirality of achiral compounds Me Me 2 H2O2, OH– Me OH
Enantiotopic face (re/si) Me Me 98.4% ee
• In general, achiral unsaturated molecules have a symmetry plane involving the double bond.
The plane has two faces. If the attack of a reagent on each face leads to forming different O O NR O OH
enantiomer, the face is called 'enantiotopic face'. + Me L-proline cat. 2 Me
・ Prochirality of enantiotopic face can be indicated with descriptor re or si. The prochirality is H H H anti/syn = 24/1
assigned as follows: Me Me Me Me Me >99% ee
i) Determine the priority of the three substitutents on the atom, which will become a chiral center
after the enantioselective reaction. 4) Differentiation of enantiotopic groups (or atoms)
ii) View the face from above. The face is called re-face when the direction of a → b → c is • In some enantioselective reactions, a chiral reagent or catalyst discriminates two enantiotopic
clockwise. Otherwise, the face is si-face. groups of a substrate to give an enantio-enriched product.
Ph2 Ph 2 Me3 • After forming the chiral product, one of the enantiotopic groups remains in the product. The
b a → b → c O O PhHC desired product will further react with the reagent, if the chiral reagent or catalyst exhibits low
c clockwise ··· re-face 3H 1 H 1NHAc stereoselectivity. However, the overreaction may lead to increasing in the enantiomeric excess
a anticlockwise ··· si-face si-face re-face re-face of the product. The enantiomeric excess of the product does not reflect the selection of the
enantiotopic groups.

– 14 –
Me Me PLE Me Me at 36% yield ··· 80% ee • By structure of the chiral substrate: The structure sometimes strongly relates to the
AcO OAc (α = k1/k2 = 2.47 ± 0.36) AcO OH at 15% yield ··· 95% ee stereoselectivity. When the reaction is known to proceed through early transition state (in
Hammond postulate), the major product can be predicted with the steric hindrance imagined
d
pro-R b If the pro-R-c is more reactive than pro-S-c from the structure of the substrate.
k1 a S k3 in 1, (S)-2 is obtained as the major product (k1 • By structures of the diastereomeric products (or intermediates): The difference in
b c 2c b d > kT2h)e. minor product (R)-2 still has pro-R-c. thermodynamic stability between the possible diastereomeric products sometimes strongly
a a The group c would be more reactive than relates to the stereoselectivity. When the reaction is known to proceed through late transition
c c d
1 k b k 3 pro-S-c remaining in (S)-2. Therefore, (R)-2 state (in Hammond postulate), the major product can be predicted with the thermodynamic
2 R 4 would be easier to be converted into achiral 3
pro-S a d (achiral) than (S)-2 (k4 > k3). stability of each possible product.

C. J. Sih, J. Am. Chem. Soc. 1984, 106, 3695. See also, S. L. Schreiber, J. Am. Chem. Soc., 1987, 109, 1525. 2) Substrate-controlled reaction
・ In the substrate-controlled reaction, the stereochemistry of the substrate predominantly controls
(b) Diastereoselective reaction the stereoselectivity.
1) Properties ・ All diastereoselective reactions are substrate-controlled reactions when they are conducted with
• Diastereoselective reaction produces a new chiral center on the substrate, which has a chiral an achiral reagent (or catalyst).
center. The diastereoselectivity reflects the ratio of the diastereoisomeric products.
O OH OH
• The stereogenic center in the substrate can control the stereochemistry of the reaction (i. e.
Zn(BH )
diastereoselectivity). Therefore, an achiral reagent can selectively produce a single Me 42 Me Me
diastereomer in diastereoselective reaction. OAr Et2O, 23°C OAr OAr
1 2
Ar = 2-MeOC H 1/2 = >99/1
O O OH OH 6 4
Ph H + MeMgBr Me– aMHe b HMe– Ph Me or Ph Me Ar = 2-(t-Bu)C6H4 1/2 = <1/D9.9 A. Nelson, Tetrah edron Lett. 1986, 27, 3091.
Me 2 Me Me OH OH OH
1 Ph 3a 3b [Rh] cat.
Et OBz Et OBz Et OBz
TSa Meδ– OδH– TSb HOδ–Mδe– TBSO Me H2, CH2Cl2, 25°C TBSO 1 Me TBSO 2 Me
Me H Me H [Rh] = Rh(dppb)+ 1/2 = 89/11
E Ph E Ph [Rh] = Rh[(R)-binap]+ 1/2 = 97/3
[Rh] = Rh[(S)-binap]+ 1/2 = 92/8
1 + 2 1 + 2 3b
3a D. A. Evans, Tetrahedron Lett. 1985, 26, 6005.

• Choice of the achiral reagent may bring about reversal of the stereoselectivity. However, such a
• The stereoselectivity in the diastereoselective reaction is often evaluated with diastereomeric reaction should be treated as a substrate-contorolled reaction, because the interaction between
excess (de, %), which is the difference between percentages of major and minor products, (de the reagent and the substrate must strongly affect the stereoselectivity.
(%) = 100([major product] – [minor product])/([major product] + [minor product]).
• There are two manners of stereocontrol in diastereoselective reaction. One is the stereocontrol O OH OH
NaBH , MCl
by the chirality of the substrate; another is that by the chirality of the reagent or catalyst. t-Bu CO2Et 4 n t-Bu CO2Et t-Bu CO2Et
MeOH, 0°C
How to predict the major product Me Me 1 Me 2
• By transition state: In principle, the stereoselectivity is controlled by the difference in energy MCln = none 1/2 = 10/90
between favorable and unfavorable transition states. Comparing the two possible transition MCln = MnCl2 1/2 = 95/5
states is useful for predicting the major product. However, it is not easy to predict structure and K. Oshima, K. Utimoto, Tetrahedron, 1993, 49, 11169.
energy of each transition state. (review) O. Reiser, Chem. Rev., 1999, 99, 1191.

– 15 –
3) Double stereodifferentiation (review) S. Masamune, Angew. Chem. Int. Ed. Engl., 1985, 24, 1. 4) Reagent-controlled reaction
• In the reaction between two chiral molecules, both of the substrates affect the stereoselectivity. • In the reagent-controlled reactions, the stereochemistry of the reagent (or catalyst)
The effect of the combination of two chiral molecules is called double strereodifferentiation. predominantly affects the stereoselectivity of the reaction.
• If the stereochemical effect of the chiral substrate is predominant over that of the reagent, the • A new chiral center possessing the desired configuration can be created on a chiral substrate
reaction should be categorized as substrate-controlled reaction. independent of its stereochemistry by choosing the enantiomeric reagent (or catalyst).
• If the effect of the chiral reagent or catalyst is predominant over that of the substrate, the reaction
should be categorized as a reagent-controlled reaction. (Substrate-controlled epoxidation)
• When the chiral substrate and reagent (or catalyst) are comparable in the effect on
O Ti(O-i-Pr) O O
stereoselectivity, the direction of asymmetric induction arising from each compound should be 4
carefully considered. O OH TBHP O OH O OH
• Diastereoselectivity of the reaction would enhance, when the directions of both asymmetric O O
1 2 1/2 = 2.3/1

induction are parallel. The combination of the substrate and reagent is called matched pair. If
(Enantioselective epoxidation (Katsuki-Sharpless oxidation))
the directions are opposite each other, the stereochemical combination is called mismatched
pair. BnO OH Ti(O-i-Pr)4, (+)-DET BnO OH
TBHP, –20°C O 99/1

(Diasteleoselective aldol reaction controlled by chiral aldehyde)
O OLi OH O OH O (Reagent-controlled epoxidation)
Cy S H + Me OTBS Cy R OTBS Cy S OTBS Ti(O-i-Pr)4, (–)-DET O
Me Me Me Me Me MeMe Me Me MeMe matched O OH
TBHP, –20°C
1 2 3 O
2/3 = 1/2.7 O 1/2 = 90/1
1
(Diasteleoselective aldol reaction controlled by chiral enolate) O OH
O OLi OH O OH O Ti(O-i-Pr)4, (+)-DET O
+ Me S OTBS Ph S OTBS Ph R OTBS mismatched TBHP, –20°C O OH
Ph H Ph4 Me Me5PhMe Me6PhMe 2O 1/2 = 1/22
5/6 = 1/3.5 S. Masamune, K. B. Sharpless J. Am. Chem. Soc., 1982, 47, 1373.
(Aldol reaction with matched pair) See also, S. Masamune, Angew. Chem. Int. Ed. Engl., 1985, 24, 1.
OLi OH O OH O
(c) How to control stereochemistry
1 + Me S OTBS Cy OTBS Cy OTBS
R S 1) Chiral reagent
Ph Me Me Me PhMe Me Me PhMe • In the reaction producing a chiral compound from an achiral substrate, the product may be
4 7 8 obtained as an optically active form, if the reagent is modified with an enantiopure substituent.
7/8 = 1/8
• The optically active reagent is called chiral reagent.
(Aldol reaction with mismatched pair)
• The reaction with the chiral reagent proceeds enantioselectively. The product does not contain
OLi OH O OH O
the chiral substituent on the chiral reagent.
1 + Me R OTBS Cy R OTBS Cy S OTBS • Stoichiometric or excess amount of the chiral reagent is required to obtain the desired chiral
Me Ph Me Me MePh Me Me MePh product with high ee.
ent-4 9 10
9/10 = 1.5/1

S. Masamune, Angew. Chem. Int. Ed. Engl., 1980, 19, 557.

– 16 –
THPO THPO The used chiral auxiliary can be recycled.
CO2Me (S)-BINAL-H CO2Me • In this case, the substrate has the chiral center stemming from the auxiliary. Therefore, the
stereoselective reaction involving the chiral auxiliary is not enantioselective reaction, but
Me THF, –100 to –78°C 15S Me
diastereoselective one.
THPO THPO
O OH • It is relatively easy to design the key intermediate involving the substrate and chiral auxiliary and
–
15S/15R = 100:0 to predict the stereochemistry of the product. Therefore, the stereoselective reaction using a
O H chiral auxiliary is frequently used in organic synthesis as compared to other methods.
Al Li+
O OEt
O O OH O O O
OH O
(S)-BINAL-H O Me Bu2BOTf H2O2
R. Noyori, J. Am. Chem. Soc., 1979, 101, 3129; 1984, 106, 6709; 1984, 106, 6717. + N O R N O R OH + HN O
R H i-Pr2NEt Me LiOH Me
2) Chiral catalyst i-Pr (R = Bu, i-Pr, Ph) i-Pr i-Pr
>99% ee (2S,3R)
• If the reaction proceeds through a catalyst, the chiral product may be obtained as an optically
D. A. Evans, J. Am. Chem. Soc., 1981, 103, 2127.
active form, if the catalyst is modified with an enantiopure substituent or compound.
• The optically active catalyst and the enantiopure ligand are called chiral catalyst and chiral ligand,
respectively. The enantioselective reaction through a chiral catalyst is called catalytic
asymmetric reaction.
• In the catalytic asymmetric reaction, a prochiral substrate (S) interacts with a chiral catalyst (C*)
to form a chiral intermediate (S–C*), which is often called catalyst–substrate complex. The
complex reacts with another substrate (or reagent) (R) to form the desired product (S–R). The
chiral catalyst is regenerated and then activates S again.
• The reagents employed in catalytic asymmetric reactions are achiral.
chiral catalyst
C* R R
S S C* S R
S C* enantioselective
prochiral catalyst–substrate chiral
substrate complex product
(diastereoisomeric)
0.05% cat.
CO2Na {Rh(cod)[(R,R)-DiPAMP]}BF4 CO2Na
+ H
2
NHAc 50% MeOH, 25°C, 4 h NHAc
(4 atm)
OMe 96% ee
P P Ph
Ph
MeO
(R,R)-DiPAMP
W. S. Kowles, J. Am. Chem. Soc., 1975, 97, 2567; Acc. Chem. Res. 1983, 16, 106.
3) Chiral auxiliary
• An achiral or racemic substrate can be modified with an enantiopure compound in order to obtain
the enantio-enriched product, when it has a reactive functional group, e.g. carboxylate, alcohol,
or amine. The enantiopure compound for the chiral modification is called chiral auxiliary.
• The chiral auxiliary can be removed with hydrolysis etc. after the desired stereoselective reaction.

– 17 –
(3) Stereochemistry in the nucleophilic addition and reduction of carbonyl groups • The nucleophile Nu attacks on the carbonyl carbon from the side
O
1) Acyclic 1,2-asymmetric induction of the smallest substituent S. S L
• Nowadays, the nucleophilic addition is believed to mostly proceed through the transition state • In the case of ketone or aldehyde bearing a polar substituent X Nu Nu
proposed by Felkin and Ahn. However, several transition state models have been proposed on the a-carbon, the polar substituent prefers to stay in the (favorable) (unfavorable)
X R
and used for illustrating the stereochemistry of the nucleophilic addition. This section describes eclipsed position of carbonyl subastituent R because of the dipole Conforth model
not only the Felkin-Ahn model but also the other transition state models. interaction between C=O and C –X (Cornforth model).
Felkin–Ahn model 2) Chelation-controlled 1,2-asymmetric induction
Nu
• In a nucleophilic addition, the nucleophile Nu • Stereoselectivity in the nucleophilic addition is often controlled by a metal
: θ Nu
donates its lone pair to the p* orbital of hyperconjugationR π* atom, when the substrate has a Lewis basic heteroatom (e.g. -OR) on its S
• Icna rthbeo ntryal ngsroitiuopn. state, the electrons shared σ* Cα O R O • Tah-cea hrbeotenr oaantdo mth ea mnde ttahle a ctoamrb ohnaysl souxfyfigcieenn ti nLteewraisc ta wciidthit yt.h e metal atom to +M OX R
X
between the nucleophile aand p* orbital X Newman projection form a chelate complex as shown in the right figure. The coordination of L
conjugate the s* orbital of C –X bond. carbonyl oxygen to metal enhances the reactivity of the substrate. chelation model
• The hyperconjugation stabilizes the transition state. • The nucleophile Nu attacks on the carbonyl carbon from the side of the (L > S, X = OR etc.)
• In the transition state, the angle of Nu–C–O (q) is ca. 110°. smaller substituent S.
• In general, the chelation-controlled reaction proceeds with the opposite stereoselectivity to the
• If the carbonyl substrate has a chiral center on its a-carbon, Felkin–Ahn-controlled reaction.
Nu Nu
the largest substituent (L) is located on the antiperiplanar
position of Nu. S M S M Me Me Me
R O O R
• To avoid the steric hindrance to the attack of the nucleophile H + BuMgBr Bu Bu
to the carbonyl, the middle (M) and smallest substituent (S) L L O –78°C OH OH 81%
are respectively located by the carbonyl oxygen and carbonyl (favorable) (unfavorable) syn anti syn : anti = 89 : 11
Felkin–Ahn model
substituent R in the favorable transition state.
(L > M > S) H. Yamamoto, J. Am. Chem. Soc. 1988, 110, 3588.
OR OR OR
polar-Felkin–Ahn model Lewis acid (LA)
• In a C–X bond, the large electronegativity of X causes decrease in the energy level of its s* H + SnBu3
CH Cl
orbital. The effect enhances the ability to accept electrons through the hyperconjugation. O 2 2 OH OH
• Therefore, an additional rule is required for predicting or explaining the stereochemistry of the syn anti
nucleophilic addition, when the electrophilic substrate has a polar substituent on its a-carbon of LA = BF3•OEt3, R = TBS syn : anti = 9 : 91 (Felkin-controlled)
carbonyl group. LA = BF3•OEt3, R = Bn syn : anti = 39 : 61
LA = MgBr , R = TBS syn : anti = 21 : 79
2
• The polar substituent X, e.g. OMe, Cl, etc., prefers the Nu Nu LA = MgBr2, R = Bn syn : anti = >250 : 1 (chelation-controlled)
antiperiplanar position of the nucleophile Nu in the G. E. Keck, Tetrahedron Lett. 1984, 25, 265.
S L S L
Felkin-Ahn transition state. R O O R
• To avoid the steric hindrance to the attack of the nucleophile 3) 1,3-Asymmetric induction
to the carbonyl, the large (L) and small substituent (S) are X X i) Chelation-controlled 1,3-asymmetric induction
(favorable) (unfavorable)
respectively located by the carbonyl oxygen and carbonyl • Stereoselectivity in the nucleophilic addition is sometimes controlled by the stereochemistry of
polar-Felkin–Ahn model
substituent R in the favorable transition state. the b-carbon of the substrate, which has a Lewis basic heteroatom on its b-carbon.
(L > S, X = polar substituent)
• The substrate readily forms a 6-membered chelate complex with a (favorable)
Cram's rule O Lewis acid possessing multiple coordination sites (e.g. TiCl4, SnCl4) Nu H
• Cram's rule is an empirical method for predicting the S M as shown in the right figure. The nucleophilic addition will occur from Me
stereochemistry of the nucleophilic addition. Nu Nu the chelate intermediate. H O TiCl4
• It is assumed that the largest substituent (L) prefers to stay in (favorable) L R (unfavorable) • The nucleophile Nu accesses the carbonyl carbon from above to HH BOn
the eclipsed position of carbonyl substituent R. avoid the steric interaction with the pseudo-axial proton at the Nu
Cram's rule
(unfavorable)

– 18 –
a-position. (4) Stereochemistry in the reaction of enolates
OBn CHO + SiMe3 TiCl4 OBn OH 1)• SEtneorelaotcehse amreis gtreyn ienr tahtee dfo frrmomat icoanr boof neynl ocloamtepso unds through the deprotonation of the a-proton with
Me CH2Cl2 Me
a base. The enolates are possible to possess geometric isomerism. The stereochemistry can
–78°C anti : syn = 95 : 5 be controlled by metal and/or reaction conditions.
M. T. Reetz, J. Am. Chem. Soc. 1983, 105, 4833.
Bu
2 Lithium enolate
OH O Bu B B NaBH OH OH OH OH
3 O O 4 • The deprotonation often proceeds through the conformation in which a C –H bond is
a
Ph Ph THF –78°C Ph Ph Ph Ph perpendicular to the carbonyl group, because the s-orbital of the C–H bond is required to interact
Ph Ph syn anti
with p*-orbital of the C=O bond in order to form the C=C bond in the resulting enolate.
syn : anti = 98 : 2
• Repulsion between R1 and R2 in the carbonyl substrate controls the E/Z selectivity of the enolate.
K. Narasaka, Tetrahedron 1984, 40, 2233.
OTBS
O 1. LDA, solvent OTBS O
E
ii) Non-chelation-controlled 1,3-asymmetric induction Me Me Z OMe Me Me
OEt 2. TBSCl OMe N N
• The nucleophilic addition (Sakurai-Hosomi reaction) provides the 1,3-anti-product with high Me
diastereoselectivity when BF is used as a promoter, although BF cannot form the chelate DMPU
3 3 in THF–45% DMPU Z : E = 93 : 7
intermediate.
in THF Z : E = 6 : 94
• In the favorable transition state, substituent R1
on the b-carbon would be located at the Nu Nu Nu O base (B) B: H B: H O–
• Tahnetip cearripbloannyalr dpoousbitlieo nb oonf dth fea cfoersm tyhle g roopuppo. site RH HO OH HR RH HO R1 R2 OR2 HR1 OH RR21 R1 R2
direction to the C–X bond to avoid the dipole (favorable) (unfavorable) Z-enolate
H H H
repulsion. X X X R. E. Ireland, J. Org. Chem. 1991, 56, 650.
• The nucleophile Nu attacks on the carbonyl R1 R1 R1 • The deprotonation is believed to proceed through Ireland’s transition state model, when lithium
(favorable) (unfavorable)
carbon from the opposite side to the dialkylamide was used as the base.
b-carbon. • Higher reaction temperature is advantageous to the formation of E-enolate. Z-Enolate may be
OBn BF OBn OH kinetically preferable, and E-enolate may be thermodynamically preferable.
CHO + SiMe3 3
Me CH2Cl2 Me O R2NLi OLi O R2NLi OLi
–78°C anti : syn = 91 : 9 Me Me Me Me
Et THF Et t-Bu THF t-Bu
M. T. Reetz, Tetrahedron Lett. 1984, 25, 729. D. A. Evans, Tetrahedron Lett. 1994, 35, 8537.
with (t-Bu)(TMS)NLi at 23°C E : Z = 94 : 6 with (t-Bu)(TMS)NLi at 23°C E : Z = 11 : 89
4) Stereochemistry in the reaction of cyclohexanone
with Ph(TMS)NLi at –78°C E : Z = 7 : 93 with Ph(TMS)NLi at –78°C E : Z = 0 : 100
• The stereoselectivity of the nucleophilic addition of cyclohexanone is strongly affected by the
L. Xie, J. Org. Chem. 1997, 62, 7516.
substituent and/or the size of the nucleophile.
• Small nucleophiles prefer the axial attack in general. Large ones prefer the equatorial attack. R2 L1 ‡
(if R1 is large, L1 is small) O N OLi
Li L2 R2
Nu R OH H R1
O O O L1L2NLi R1 H Z-enolate
t-Bu + Nu t-Bu t-Bu OH t-Bu R R2
(nucleophile) axial-attack equatorial-attack R1 L1 ‡
Nu OLi
OH N
Nu = LiAlH4 (R = H) 90 : 10 Li L2 R1
NNuu == LMi(esL-iB (uR) 3=B HM e(L) -selectride) (R = H) 1221 :: 8789 (if R1 is small, L1 is large) R1 R2 H R2
Nu = MeLi (with MAD) (R = Me) 99 : 1 E-enolate
H. Yamamoto, J. Am. Chem. Soc. 1985, 107, 4573. R. E. Ireland, J. Am. Chem. Soc. 1976, 98, 2868.

– 19 –
Soft enolization T. Mukaiyama, Chem. Lett. 1976, 559: Bull. Chem. Soc. Jpn. 1980, 53, 174. • The carbonyl oxygen of the oxazolidinone can bond to the metal atom of the enolate. The
• Ketones and thioesters can be transformed into their enolates in the presence of a tertiary amine chelation fixes the conformation of the enolates.
and a Lewis acid (soft enolization). The interaction between the carbonyl oxygen and the Lewis • Electrophiles preferentially approaches the enolate to avoid the steric hindrance of the
acid facilitates the deprotonation of the a-hydrogen. substituent R.
• The soft enolization is useful for preparing boron, tin, silicon, titanium, magnesium enolates. • Various electrophiles are possible to react with the chiral enolate to give the optically active
• Stereochemistry of the boron enolate can be controlled by choosing the boron Lewis acid. a-substituted carboxylates with high enantiomeric excesses.
Z-Enolate will be selectively formed when two alkyl substituents on the boron atom are relatively
small. O O R2NM O MO O O
• Torfi fEla-teen oorla ioted.i de is favorable for the formation of Z-enolate. Chloride is favorable for the formation O N R (M = Li, Na, K) O N R El (electrophile) O N R
or
(c-Hex) B El
9-BBN O BOTf O (c-Hex)2BCl 2 O R' TiCl4, i-Pr2NEt R' R'
Ph Z Me Et3N Ph Me Et3N Ph EMe E(Rl:' = Bn or i-Pr) O >90% de
Z : E = >97 : <3 Z : E = <3 : >97 (X R= BrX or I) ArSO2N3 BocN NBoc Ph N SO2Ph
H. C. Brown, J. Org. Chem. 1993, 58, 147. (R–X) D. A. Evans, J. Am. Chem. Soc. 1982, 104, 1737; 1990, 112, 8215.
R2 X H NR ‡ (ArSO2N3) D. A. Evans, J. Am. Chem. Soc. 1990, 112, 4011.
B R3N 3 OBR22 (BocN=NBoc) D. A. Evans, Tetrahedron 1988, 44, 5525.
(if R2 is small)R2 O R1 O BR2 X Me (Davis reagent) D. A. Evans, J. Am. Chem. Soc. 1985, 107, 4346.
Me H Me 2 R1
R1
O R2 BX Z-enolate Enders’s hydrazone (SAMP/RAMP)
2
Me • SAMP and RAMP are prepared from (S)-proline and (R)-glutamic acid, respectively. These
R1
X H NR ‡ OBR2 hydrazones can form chiral hydrazones with an achiral ketone or aldehyde.
B R2 R3N 3 2 • The hydrazones are readily deprotonated with lithium dialkylamides to give their azaenolates.
(if R2 is large) O R2 R1 O BR22X R1 Coordination of the methoxy group to lithium fixes the conformations of the azaenolates.
R1 Me Me H Me • Electrophiles react with the azaenolates from the same side of the MeO group to avoid the steric
Z-enolate hindrance of the pyrrolidine ring.

El MeO
MeO R O
2) Stereochemistry in the reaction of chiral enolates with electrophiles 2
Cyclohexanone enolate O SAMP N LiNR2 R2O Li N N El N N
• The enolates of cyclohexanones take a half-chair conformation. The substituent on the R1 R2 N R2 Me O R1 R2 R1 El
cyclohexene ring prefers an equatorial position. R1
El R2
• An electrophile preferentially approaches the enolate from above in order to avoid the steric
O
hindrance of the pseudo-axial proton. 3
O O N N O
I Me H CO Me OMe OMe
CO2Me LiNH2 t-Bu Me I t-Bu Me Me2 NH2 NH2 R1 R2
H = SAMP RAMP
t-Bu C236H °C6 MIeOM2eCH OLi MeO2C O t-Bu D. Enders, Angew. Chem., Int. Ed. Engl. 1976, 15, 549; (review) Tetrahedron 2002E, l58, 225 3.

M. E. Kuehne, J. Org. Chem. 1970, 35, 171.
Evans’s oxazolidinone
• Optically active oxazolidinones, which are readily prepared from b-amino alcohols and phosgene,
are widely used as the chiral auxiliaries for carboxylate enolates.
• In general, the N-acyloxazolidinone gives its Z-enolate through deprotonation.

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(5) Stereoselective aldol reaction • In the aldol reactions through Zimmerman–Traxler transition state, Z-enolates selectively yield
1) Problems in aldol reaction syn-product. Anti-aldols are preferentially obtained from E-enolates.
• Aldol reaction is the reaction of an enolate with an aldehyde or a ketone, giving b-hydroxy O OH
9-BBN-Cl OB 1. PhCHO
carbonyl compound (aldol).
Me Ph Ph
• Chemoselectivity OH O OH O O i-Pr2NEt Ph>99% (Z) 2. H2O2 Me 98% syn
Me
O + O H3C CH3 H3C CH3 CH3 Ph (c-Hex) BCl OB 1. PhCHO O OH
H3C H H3C CH3 OH O OH O 2 Ph Ph Ph
Et N 2. H O
3 2 2
H C H H C H Me Me 95% anti
3 3 CH
3 >99% (E)

• Regioselectivity in the formation of enolate
H. C. Brown, J. Am. Chem. Soc. 1989, 111, 3441.
OH O
O O OH O R1 ‡ R1
TPhhese pHrob+leHm3sC are solCveHd3 by preformed enPolhate. FormatioCnH 3of mPhore suCbHs3tituCteHd3 enolate is R1O M R2 + R3CHO H R2R3HOOM R1O R2OHR3 H R2HR3OOM
thermodynamically favored. Formation of less substituted enolate is kinetically favored. Z-enolate (favorable) syn-aldol (unfavorable)
O OSiMe3 OSiMe3
Me Me Me O M R1H ‡ O OH R1R3
M M
R1 + R3CHO R2 OO R1 R3 R2 OO
(kinetically favored) (thermodynamically favored) R2 H R3 R2 H H
(1) LDA, THF, –78°C (2) Me3SiCl, –78°C to rt 99 : 1 E-enolate (favorable) anti-aldol (unfavorable)
Et N, Me SiCl, DMF, 130°C, 90 h 12 : 88
3 3 H. E. Zimmerman, J. Am. Chem. Soc. 1956, 79, 1920.
H. O. Hause, J. Org. Chem. 1969, 34, 2324. (modified method) 第4版 実験化学講座24, p 154.
• Diastereo- and enantioselectivities (stereoselectivity) Aldol reactions through open transition state model
OH O OH O • If the metal atom of enolate cannot interact with the carbonyl oxygen, their aldol reaction
proceeds through the antiperiplanar transition state, in which the dipole of C=O is arrayed to
Ph Ph Ph Ph
O O CH CH avoid the repulsion of the dipole of C–OSi.
+ CH 3 3 • Both of E- and Z-enolates selectively give the syn-aldol product, because the stereochemistry is
Ph H Ph 3 OH O OH O mainly controlled by the steric repulsion between R2 and R3.
Ph Ph Ph Ph
CH3 CH3 Me3SiO H ‡ O OH
OSiMe3 F– Me
2) Stereocontrol of vicinal chiral centers of the aldol product Ph Me + PhCHO PhPh O Ph Ph SiO R3
• In the aldol reactions of prochiral enolates with carbonyl compounds, the aldol products have H Me R2
vicinal chiral centers. The stereochemistry of the vicinal chiral centers is often controllable. syn : anti = 95 : 5 R1
Aldol reactions through Zimmerman-Traxler transition state OSiMe3 F– Ph H Me ‡ O OH H H O
• The electrophilic substrate is activated by the interaction between its carbonyl oxygen and the Ph + PhCHO Me3SiO Ph Ph (unfavorable)
Ph O
metal atom of enolate, when the enolate has a strong Lewis acidic metal. The complexation Me H Me
allows the intramolecular aldol reaction through 6-membered transition state (Zimmerman– syn : anti = 94 : 6

Traxler transition state).
R. Noyori, J. Am. Chem. Soc. 1981, 103, 2106; 1983, 105, 1598.

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3) Stereocontrol with the chiral center of the electrophilic substrate (aldehyde) • In the aldol reaction of Z-enolate, the matched-pair transition state is unfavorable because of the
• In the aldol reactions of chiral a-substituted aldehydes, the stereochemistry is controlled by syn-pentane interaction between the enolate a-substituent and the middle-sized a-substituent of
Felkin–Ahn or chelate model. aldehyde. Therefore, the stereoselectivity varies along with the substituent R of the aldehyde.
R'
H
Felkin–Ahn-controlled aldol reaction M O OH
OTBS O BF •Et O O OH O OH Felkin (matched pair) H OO R
+ H Ph 3 2 t-Bu Ph t-Bu Ph H R R'
t-Bu Me Me Me
Me Me Me O syn-pentane Me syn, syn
(Felkin–sAyhnn) : (aanntti-iF e=lk in2–4A :h n1) OM Me + H R interaction
R'
C. H. Heathcock, J. Am. Chem. Soc. 1983, 105, 1667. Z Me H
Polar-Felkin–Ahn-controlled aldol reaction R R' O OH
O O OH O OH Me O M R
OLi H R'
+ H Ph t-Bu Ph t-Bu Ph anti-Felkin (mismatched pair) H O Me Me
t-Bu OMe OMe OMe Me 2,3-syn, 3,4-anti
syn : anti = 17 : 83 • In the aldol reaction of E-enolate, the matched-pair transition state is favorable. Therefore, the
(anti-Felkin–Ahn) (Felkin–Ahn) aldol reaction generally proceeds through Felkin-Ahn transition state to give (2,3-anti,
C. H. Heathcock, J. Am. Chem. Soc. 1987, 109, 3353. 3,4-syn)-product with good selectivity.
Chelation-controlled aldol reaction R'
OTBS + H O Me TiCl4 or SnCl4 t-Bu O OH Me t-Bu O OH Me Felkin (matched pair) Me HOOM O OH R
t-Bu –78°C H R R'
OBn OBn OBn
H Me Me
syn : anti = >95 : 5
OM O Me 2,3-anti, 3,4-syn
(anti-Felkin–Ahn) (Felkin–Ahn)
E + R
M. T. Reetz, Tetrahedron Lett. 1984, 25, 729. R' H
Double stereodifferentiation: Felkin–Ahn model and Zimmerman–Traxler model Me Me H
• Reactions of Z- and E-enolates R R' O OH
OLi Me O M R
O TMSO Me O OH O OH anti-Felkin (mismatched pair) MeH O R' Me Me
R Me Me TMSO R TMSO R H anti, anti
H
Me Me Me Me Me Me Me Me Me W. Roush, J. Org. Chem. 1991, 56, 4151.
Double stereodifferentiation: polar-Felkin–Ahn model vs Zimmerman–Traxler model
Felkin product (syn,syn) anti-Felkin product (syn,anti)
• Reactions of Z- and E-enolates
R = Ph (syn, syn) : (syn, anti) = 81 : 19 OB O O OH O OH
RR == Cc-HC26OHA11c ((ssyynn,, ssyynn)) :: ((ssyynn,, aannttii)) == 2271 :: 7739 i-Pr Me + H Me i-Pr Me i-Pr Me
Z
OTBS Me OTBS Me OTBS
OLi
O ArO OH OH Felkin 98 : 2 anti-Felkin
H Ph Me ArO2C Ph ArO2C Ph OB O O OH O OH
Me Me Me Me Me i-Pr E + H Me i-Pr Me i-Pr Me
Felkin product anti-Felkin product
(anti,syn) (anti,anti) Me OTBS Me OTBS Me OTBS
Felkin anti-Felkin
80 : 20 21 : 79

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